Duloxetine and related class of compounds like fluoxetine, tomoxetine etc., are important for treating psychiatric disorders. Fluoxetine is a selective inhibitor of serotonin in serotonergic neurons, tomoxetine and nisoxetine are selective inhibitors of norepinephrine in noradrenergic neurons while duloxetine is a dual inhibitor of serotonin and norepinephrine reuptake and thus have a better pharmacological profile as an antidepressant drug (EP 273658, 1988; Chem. Abstr., 1988, 109, 170224n; Life Sci 1988, 43, 2049).
Serotonin and norepinephrine neuro transmitters are intimately involved in a number of physiological and behavioral processes, suggesting that duloxetine (ability to produce robust increase of extra cellular serotonin and norepinephrine levels) is not only a highly efficient antidepressant agent for treating psychiatric disorders but also can be used for treating other symptoms like alcoholism, urinary incontinence, fatigue, stroke, intestinal cystitis, obsessive compulsive disorder, panic disorder, hyperactivity disorder,11 sleep disorder, sexual dysfunction etc.
Duloxetine having one chiral center can exist in two isomeric forms. In view of the different pharmacological activities displayed by individual enantiomers, differences in metabolic behaviour and importance to provide enantiomerically pure forms as drugs, the preparation of this drug in enantiomerically pure form is highly desirable.
Duloxetine has the basic structural skeleton of 3-amino-propanol and retrosynthetic synthetic strategy reveals that enantiomerically pure 3-hydroxy-3-(2-thienyl) propanenitrile (β-hydroxy nitrile) (1) should be an excellent chiral building block for the synthesis of the target molecule. In the literature, there are only few reports for the synthesis of duloxetine in optically pure form, one by employing complexed-LAH for asymmetric reduction of the Mannich base (Tetrahedron Lett. 1990, 31, 7101) and other by lipase mediated resolution of 3-chloro-1-(2-thienyl)-1-propanol (Chirality 2000, 12, 26).
